Winder Lab

Alpha1-adrenergic receptor-induced heterosynaptic long-term depression in the bed nucleus of the stria terminalis is disrupted in mouse models of affective disorders.

AUTHORS

ABSTRACT

The glutamatergic synapse in specific brain regions has been shown to be a site for convergence of stress and addictive substances. The bed nucleus of the stria terminalis (BNST), a nucleus that relays between higher order processing centers and classical reward and stress pathways, receives dense noradrenergic inputs that are known to influence behavioral paradigms of both anxiety and stress-induced relapse to drug seeking. Alpha(1)-adrenergic receptors (alpha(1)-ARs) within this region have been implicated in modulation of the HPA axis and anxiety responses. We found that application of an alpha(1)-AR agonist produced a long-term depression (LTD) of excitatory transmission in an acute mouse BNST slice preparation. This effect was mimicked by a 20 min, but not a 10 min, application of 100 microM norepinephrine (NE) in a prazosin-sensitive manner. This alpha(1)-AR LTD was independent of N-methyl-D-aspartate receptor (NMDAR) function unlike previously described alpha(1)-AR LTD in the hippocampus and visual cortex; however, it was dependent on the activation of L-type voltage gated calcium channels (VGCCs). In addition, alpha(1)-AR LTD was induced independently of the activation of mGluR5 which can also induce LTD in this region. Furthermore, alpha(1)-AR LTD was intact in mice receiving an intraperitoneal injection of cocaine but was disrupted in alpha(2a)-AR and NE transporter (NET) knockout (KO) mice. Thus a loss of this plasticity at glutamatergic synapses in BNST could contribute to affective behavioral phenotypes of these mice.